Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whilst previously type 2 diabetes occurred in older adults, its incidence, together with obesity, has increased rapidly in children. An improved understanding of this disease pathway from a developmental view point is critical. It is likely that subtle changes in dietary patterns over an extended period of time contribute to diabetes, although this type of rationale is largely ignored in animal studies aimed at determining the mechanisms involved. Small-animal studies in which large, and often extreme, changes in the diet are imposed at different stages of the life cycle can have substantial effects on fat mass and/or pancreatic functions. These responses are not representative of the much more gradual changes seen in the human population. An increasing number of studies indicate that it is growth rate per se, rather than the type of dietary intervention that determines pancreatic function during development. Epigenetic mechanisms that regulate insulin secretion by the pancreas can be re-set by more extreme changes in dietary supply in early life. The extent to which these changes may contribute to more subtle modulations in glucose homeostasis that can accompany excess fat growth in childhood remains to be established. For human subjects there is much less information as to whether specific dietary components determine disease onset. Indeed, it is highly likely that genotype has a major influence, although recent data relating early diet to physical activity and the FTO gene indicate the difficulty of establishing the relative contribution of diet and changes in body mass to diabetes.
 ...
PMID:Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Diabetes and health". Nutrition and its contribution to obesity and diabetes: a life-course approach to disease prevention? 1906 49

Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1 and PCSK1). Here we extend those studies by examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3885 non-diabetic and 1038 diabetic individuals with available measures of height, weight and body mass index (BMI). Adipose mass and distribution were objectively assessed using dual-energy X-ray absorptiometry in a sub-group of non-diabetics (n = 2206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P < 0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752 and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the score were heavier (+2.6 kg) and had more total (+2.4 kg), gynoid (+191 g) and abdominal (+136 g) adipose tissue than those in the lowest quintile (all P < 0.001). The genetic burden score significantly increased diabetes risk, with those in the highest quintile (n = 193/594 cases/controls) being at 1.55-fold (95% CI 1.21-1.99; P < 0.0001) greater risk of type 2 diabetes than those in the lowest quintile (n = 130/655 cases/controls). In summary, we have statistically replicated six of the previously associated obese-risk loci and our results suggest that the weight-inducing effects of these variants are explained largely by increased adipose accumulation.
 ...
PMID:Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden. 1916 86

Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20-24% of the populations), subjects with three or four risk alleles (7-10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (approximately 1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm(3) (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.
 ...
PMID:Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. 1925 36

Here we explore whether there is any evidence that the rapid development of the obesity epidemic in emerging nations, and its unusual coexistence with malnutrition, may have evolutionary origins that make such populations especially vulnerable to the obesogenic conditions accompanying the nutrition transition. It is concluded that any selection of so-called 'thrifty genes' is likely to have affected most races due to the frequency and ubiquity of famines and seasonal food shortages in ancient populations. Although it remains a useful stimulus for research, the thrifty gene hypothesis remains a theoretical construct that so far lacks any concrete examples. There is currently little evidence that the ancestral genomes of native Asian or African populations carry particular risk alleles for obesity. Interestingly, however, there is evidence that a variant allele of the FTO gene that favors leanness may be less active in Asians or Africans. There is also some evidence that Caucasians may be less prone to developing type 2 diabetes mellitus than other races suggesting that there has been recent selection of protective alleles. In the near future, recently developed statistical methods for comparing genome-wide data across populations are likely to reveal or refute the presence of any thrifty genes and might indicate mechanisms of vulnerability.
 ...
PMID:Obesity in emerging nations: evolutionary origins and the impact of a rapid nutrition transition. 1934 67

We investigated the association between the rs9939609 (T>A) polymorphism in the FTO (fat mass- and obesity-associated) gene and obesity- and type 2 diabetes mellitus-related phenotypes in the French Multinational MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA) Study (n = 3367). In the study, TA or AA subjects had higher body mass index (BMI) (P = .017), waist circumference (P = .017), and hip (P = .01) circumference in an A allele dose-dependent manner. The A allele was also significantly associated with higher plasma insulin levels (P = .05), higher insulin resistance index (homeostasis model assessment) (P = .02), and higher systolic blood pressure (P = .003); but these associations disappeared after adjustment for BMI. In the study, 598 subjects were obese (BMI >or=30 kg/m(2)); and 2769 subjects were not obese (BMI <30 kg/m(2)). Subjects bearing the A allele of rs9939609 had a higher risk of obesity (adjusted odds ratio [95% confidence interval] = 1.29 [1.06-1.58], P = .01) compared with TT subjects. Moreover, the homozygous AA genotype of rs9939609 was associated with a higher risk of type 2 diabetes mellitus (odds ratio = 1.45 [1.05-1.99], P = .02, 283 subjects with and 2601 subjects without type 2 diabetes mellitus), independently of BMI. In conclusion, the role of the A allele of the FTO rs9939609 polymorphism on the risk of obesity and type 2 diabetes mellitus was confirmed in the French MONICA Study.
 ...
PMID:Effect of an FTO polymorphism on fat mass, obesity, and type 2 diabetes mellitus in the French MONICA Study. 1937 60

Human FTO gene variants are associated with body mass index and type 2 diabetes. Because the obesity-associated SNPs are intronic, it is unclear whether changes in FTO expression or splicing are the cause of obesity or if regulatory elements within intron 1 influence upstream or downstream genes. We tested the idea that FTO itself is involved in obesity. We show that a dominant point mutation in the mouse Fto gene results in reduced fat mass, increased energy expenditure, and unchanged physical activity. Exposure to a high-fat diet enhances lean mass and lowers fat mass relative to control mice. Biochemical studies suggest the mutation occurs in a structurally novel domain and modifies FTO function, possibly by altering its dimerisation state. Gene expression profiling revealed increased expression of some fat and carbohydrate metabolism genes and an improved inflammatory profile in white adipose tissue of mutant mice. These data provide direct functional evidence that FTO is a causal gene underlying obesity. Compared to the reported mouse FTO knockout, our model more accurately reflects the effect of human FTO variants; we observe a heterozygous as well as homozygous phenotype, a smaller difference in weight and adiposity, and our mice do not show perinatal lethality or an age-related reduction in size and length. Our model suggests that a search for human coding mutations in FTO may be informative and that inhibition of FTO activity is a possible target for the treatment of morbid obesity.
 ...
PMID:A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. 1968 May 40

The pathophysiology of latent autoimmune diabetes in adults (LADA) is considered less understood than its much better characterized counterparts of type 1 and type 2 diabetes (T1D and T2D), where its clinical presentation exhibits some features of each of these two main diseases, earning it a reputation as being "type 1.5 diabetes". The etiology of LADA remains unknown, but a genetic component has been implicated from recent reports of T1D and T2D genes playing a role in its pathogenesis. One way to shed much needed light on the classification of LADA is to determine the discrete genetic factors conferring risk to the pathogenesis of this specific phenotype and to determine to what extent LADA shares genetic similarities with T1D and T2D. For instance, no conclusive support for a role of the T1D-associated INS gene has been reported in T2D; conversely, but similarly, no evidence has been found for the role of the T2D-associated genes IDE/HHEX, SLC30A8, CDKAL1, CDKN2A/B, IGF2BP2, FTO, and TCF7L2 in T1D. However, and somewhat at odds with current thinking, TCF7L2, the most strongly associated gene with T2D to date, is strongly associated with LADA, a disorder considered by the World Health Organization to be a slowly progressing form of T1D. In this review, we address recent advances in the genetics of T1D and T2D and how such discoveries have in turn shed some light on the genetics of LADA as being potentially at the "genetic intersection" of these two major diseases.
 ...
PMID:Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? 2000 22

Obesity has become an epidemic in many countries and is one of the major risk conditions for disease including type 2 diabetes, coronary heart disease, stroke, dyslipidemia, and hypertension. Recent genome-wide association studies have identified two genes (FTO and near MC4R) that were unequivocally associated with body mass index (BMI) and obesity. For the Genetic Analysis Workshop 16, data from the Framingham Heart Study were made available, including longitudinal anthropometric and metabolic traits for 7130 Caucasian individuals over three generations, each with follow-up data at up to four time points. We explored the associations between four single-nucleotide polymorphisms (SNPs) on FTO (rs1121980, rs9939609) or near MC4R (rs17782313, rs17700633) with weight and BMI under an additive model. We applied multilevel linear mixed model for continuous outcomes, using the Affymetrix 500k genome-wide genotype data for the four SNPs. The results of the multilevel modeling in the entire sample indicated that the minor alleles of the four SNPs were associated with higher weight and higher BMI. The most significant associations were between rs9939609 and weight (p = 4.7 x 10-6) and BMI (p = 8.9 x 10-8). The results also showed that, for SNPs at FTO, the homozygotes for the minor allele had the most pronounced increase in weight and BMI, while the common allele homozygotes gained less weight and BMI during the follow-up period. Linkage disequilibrium (LD) between the two FTO SNPs was strong (D' = 0.997, r2 = 0.875) but their haplotype was not significantly associated with either weight or BMI. The two SNPs near MC4R were in weak LD (D' = 0.487, r2 = 0.166).
 ...
PMID:A multilevel linear mixed model of the association between candidate genes and weight and body mass index using the Framingham longitudinal family data. 2001 80

Several common variants in the intron 1 of FTO (fat mass and associated obesity) gene have been reliably associated with BMI and obesity in European populations. We analyzed two variants (rs9939609 and rs8050136) in 4,189 Chinese Han individuals and conducted a meta-analysis of published studies in Asian population to investigate whether these variants are associated with type 2 diabetes (T2D) and obesity in Asian population. In this study, both the minor allele A of rs9939609 and the minor allele A of rs805136 were associated with increased risk of T2D, independent of measures of BMI; the odds ratios (ORs) per copy of the risk allele were 1.19 for rs9939609 (95% confidence interval (CI), 1.04-1.37; P = 0.01) and 1.22 for rs8050136 (95% CI, 1.07-1.40; P = 0.004) after adjusting for age, sex, and BMI. Our results also showed association with risk of obesity (rs9939609: OR = 1.39 (95% CI 1.04-1.85), P = 0.02; rs8050136: OR = 1.45 (95% CI 1.09-1.93), P = 0.01) but no association with overweight. These results were consistent with the pooled results from our meta-analysis study (for diabetes, rs8050136, P = 1.3 x 10(-3); rs9939609, P = 9.8 x 10(-4); for obesity, rs8050136, P = 2.2 x 10(-7); rs9939609, P = 9.0 x 10(-9)). Our findings indicate that the two variants (rs9939609 and rs8050136) in the FTO gene contribute to obesity and T2D in the Asian populations.
 ...
PMID:Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the Asian population. 2127 10

Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes.
 ...
PMID:Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. 2008 Jul 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>